NEURONAL SIGNAL TRANSDUCTION:
LOCAL REGULATION OF SYNAPTIC
STRENGTH AT AN EXCITATORY
SYNAPSE
Glutamate released at excitatory synapses can bind to
several different classes of receptors including
ligand regulated ion channels for sodium
(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AMPAR) and
calcium (N-methyl-D-aspartate receptor; NMDAR), as well as several types
of G-protein coupled metabotropic glutamate receptors (mGluRs).
Repeated firing
at such synapses results in modulation of synaptic strength through several
mechanisms, including increased levels of the second messenger Ca+2
via NMDAR, which enhances AMPAR action by activation of a calciumcalmodulin
kinase II (CaMKII) dependent pathway resulting in AMPAR phosphorylation and
increased AMPAR recruitment and stabilization.
Group I mGluR are generally
found
on postsynaptic sites and can further increase
synaptic strength by Gq-mediated activation of phospholipase C gamma 1 (PLCγ1),
leading to production of inositol 1,4,5-triphosphate (IP3) and release of
calcium from endoplasmic reticulum (ER) stores by activation of the inositol
1,4,5-triphosphate receptor (IP3R). In contrast, groups II and III mGluRs, which
are typically present on presynaptic sites, lead to decreased release of
glutamate via their G-protein coupled second messengers, resulting in feedback
inhibition of the process. Other factors such as brain-derived neurotrophic
factor (BDNF) can modulate glutamatergic signaling by activating tropomyosin
receptor kinase B (TrkB), resulting in activation of PLCγ1 and IP3-dependent calcium release from the ER.
